JPH0425966B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to a thermoplastic elastomer having excellent antithrombotic properties. Polymer materials are originally foreign substances to living organisms, and when blood comes into contact with foreign substances, plasma proteins are adsorbed, and platelets subsequently adhere and aggregate to form a thrombus. Therefore, the first condition for medical polymer materials that come into contact with blood is that they must have antithrombotic properties. Specific examples include materials for artificial hearts, auxiliary artificial hearts, vascular catheters, blood bags, blood pumps, and the like. [Prior Art] Many such materials have been proposed, but segmented polyurethane is particularly superior in terms of mechanical strength and antithrombotic properties.
A copolymer of polysiloxane and polyurethane described in Ethicon's Biomer, US Pat. No. 3,562,352 is commercially available under the trade name Cardiothane. Also, in the published patent publication 1985-211358,
Polyurethane or polyurethane urea containing an organosilicon polymer in the main chain has been proposed as a new antithrombotic elastomer that has both antithrombotic properties and mechanical properties. [Problems to be Solved by the Invention] On the other hand, as many clinical examples of antithrombotic materials are accumulated, there is an increasing desire for better antithrombotic materials. For example, according to clinical examples of auxiliary hearts using segmented polyurethane and cardiothane, when the role of the auxiliary heart is reduced to reduce blood flow as the heart recovers, or when the stroke volume of the blood pump changes. It has been reported that there is a risk of thrombus formation, and that there is a tendency for calcium and phosphorous to be deposited when a blood pump with a small pump capacity is used to ensure blood flow rate. (For example, 13th Medical Polymer Symposium Abstracts P29 (1984) University of Tokyo, Kazuhiko Atsumi et al. "Evaluation of antithrombotic properties of clinical artificial heart pumps") [Means for solving the problem] The present inventors From the above viewpoint, we conducted a series of studies on block copolymers and graft copolymers with a microphase-separated structure, which are said to be promising as antithrombotic materials. It has been shown that segmented polyurethanes forming polyurethanes, especially polyurethanes or polyurethane ureas containing soft segments derived from poly(oxy-2-methyl-1,3-propane) diol and polyorganosiloxane, exhibit excellent antithrombotic properties. Thus, we have arrived at the present invention. That is, the present invention produces soft segments by reacting organic diisocyanate with poly(oxy-2-methyl-1,3-propane) diol having a number average molecular weight of 200 to 3000 and polyorganosiloxane having a number average molecular weight of 200 to 3000. The present invention provides a method for producing a thermoplastic antithrombotic elastomer, characterized in that the content of polyurethane or polyurethane urea is 40 to 70% by weight. In the thermoplastic antithrombotic elastomer of the present invention, the soft segment content is preferably 40 to 70% by weight, and furthermore, poly(oxy-2-methyl-1,3-
The content of soft segments produced from propane) diol is 20 to 50% by weight, and the content of soft segments produced from polyorganosiloxane is 5% by weight.
Preferably it is ~30% by weight. Poly(oxy-2-methyl-1,3-propane)diol is produced by converting 2-methyl-1,3-propanediol to 3-methyl oxetane as described in JP-A-58-126828. The poly(oxy-2-methyl-1,3-propane) diol obtained by cationic ring-opening polymerization and particularly used in the present invention preferably has a number average molecular weight of 200 to 3000, more preferably 400 to 2000. be. This is because if the number average molecular weight is less than 200, the microphase separation tendency, which is one of the characteristics of the antithrombotic elastomer of the present invention, will be incomplete, and if it is more than 3,000, the expression of antithrombotic properties will be impaired. It is also possible to replace some of the oxy-2-methyl-1,3-propane units of poly(oxy-2-methyl-1,3-propane) diol with other oxy-alkylene units, such as oxytetramethylene units. However, from the viewpoint of antithrombotic properties, it is desirable that the content of oxy-2-methyl-1,3-propane units is at least 80 mol% or more. These poly(oxy-2-methyl-1,3-propane) diols have hydrophobic methyl groups in their side chains, and unlike poly(oxytetramethylene) diols and polyethylene glycols, they are essentially amorphous and segmented. Together with the contribution of the hydrophobic poly-organo-siloxane, which is easily movable and is incorporated into polyurethane or polyurethane-urea (described later), it migrates to the air-contacting surface with low surface free energy, imparting antithrombotic properties. It provides a polymer surface with a suitable hydrophilic-hydrophobic balance and a microphase-separated higher-order structure. Furthermore, unlike the case of poly(oxy-1,2-propane) diol, which has primary and secondary hydroxyl groups, poly(oxy-2-methyl-1,3-
Propane) diol has high co-reactivity at both ends 1
Because of its hydroxyl group, when converted into urethane or urethane/urea, it provides polyurethane or polyurethane/urea with high molecular weight and excellent mechanical properties, and its major feature is that it is easy to design block or graft structures. Motsu. The polyorganosiloxane used in the present invention includes polydimethylsiloxane, polymethylphenylsiloxane, polydiphenylsiloxane, polyfluoroalkylsiloxane, etc., but since it does not have bulky groups, it has the characteristics of polysiloxane. Polydimethylsiloxane, which is easily released, is preferred. Furthermore, in order to incorporate these polyorganosiloxanes into a polymer chain through a urethane bond or a urethane-urea bond, it is desirable to have carbinol groups or amino groups at both ends. The molecular weight of the polyorganosiloxane used is the poly(oxy-2-methyl-
For the same reason as in the case of 1,3-propane diol, a number average molecular weight of 200 to 3000 is desirable. Next, a method for synthesizing polyurethane or polyurethane urea containing a soft segment produced from poly(oxy-2-methyl-1,3-propane) diol and polyorganosiloxane will be described. Generally, polyurethane or polyurethane urea is synthesized by the one-shot method, in which each component is charged into a reaction vessel at once and reacted, or by the one-shot method in which poly(oxy-2-methyl-1,
There is a prepolymer method in which a prepolymer of 3-propane diol and polyorganosiloxane is synthesized and chain extended using a short-chain diol or diamine to synthesize polyurethane or polyurethane urea. A simple prepolymer method is suitable. That is, in the one-shot method, the distribution of so-called hard segment chain lengths including urethane bonds, urethane urea bonds, etc. becomes large, making it difficult to control the domain size of the microphase-separated structure. The organic diisocyanate used is not particularly limited, and any organic diisocyanate that is normally used to obtain polyurethane polymers may be used. That is, the aromatic diisocyanates include 2,6-tolylene diisocyanate, 2,4-tolylene diisocyanate, 4,
4'-diphenylmethane diisocyanate, 1,5
- Naphthalene diisocyanate, m-xylylene diisocyanate, p-xylylene diisocyanate, m-phenylene diisocyanate, p-phenylene diisocyanate, tolidine isocyanate, etc. are used, and as the aliphatic diisocyanate, 1,6-hexamethylene diisocyanate,
1,10-decamethylene diisocyanate, isophorone diisocyanate, bis(isocyanatomethyl)cyclohexane, dicyclohexylmethane diisocyanate, trimethylhexamethylene diisocyanate, toridine diisocyanate, etc. can be used. However, from the viewpoint of mechanical properties of the resulting polyurethane or polyurethane urea, aromatic diisocyanates, particularly 4,4'-diphenylmethane diisocyanate, are preferred. As a chain extender, a compound having a bifunctional active hydrogen group, such as ethylenediamine, propylenediamine, butylenediamine, hexamethylenediamine, cyclohexanediamine, piperazine, phenylenediamine, diphenylmethanediamine,
Aliphatic or aromatic diamines such as xylylene diamine, aliphatic diols such as ethylene glycol, propylene glycol, butylene glycol, and others such as ethanolamine and hydrazine can be used. In order to impart an antithrombotic function, it is preferable that the elastomer be accompanied by significant cross-linking, and is preferably an elastomer that is essentially thermoplastic. Therefore, trifunctional compounds such as trimethylolpropane, glycerin, or N, N, N',
If a tetrafunctional compound such as N'-tetrakis(2-hydroxypropyl)ethylenediamine is used, it must be used within a range that does not impair thermoplasticity. In addition, in order to prevent secondary crosslinking and to allow the reaction to proceed sufficiently in a homogeneous system, it is preferable to perform the reaction in a solution system, and as a solvent, dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, Dioxane, tetrahydrofuran, etc. are used. Highly reactive components such as aliphatic diamines react well even at room temperature to give polyurethane urea, but it is generally better to warm them up somewhat in order to make the reaction proceed smoothly. The reaction usually occurs easily without the use of a catalyst, but when used, a catalyst that can be easily removed from the polymer, such as triethylamine, dimethylethanolamine, or 1,8-diaza-bicyclo[5,4,0]7-undecene, is used. It is necessary to use The resulting solution of polyurethane or polyurethaneurea may be poured into a large amount of water to precipitate into flakes, washed with water, methanol, and ethanol, and then dried. In conducting the platelet adhesion test, further purification is performed by Soxhlet extraction using ethanol. The evaluation method will be described later. [Effect] Next, the relationship between thermoplastic elastomer composition and antithrombotic properties will be explained. The content of polyorganosiloxane block is 5 to 30% by weight based on the total amount of elastomer, and the content of poly(oxy-2-methyl-1,3-propane) block is 20 to 50% by weight based on the total amount of elastomer.
The soft segment component expressed as the sum of the polyorganosiloxane block and poly(oxy-2-methyl-1,3-propane) block is preferably 40 to 70% by weight based on the total amount of the elastomer. The amount of the soft segment component is limited by the mechanical properties of the thermoplastic elastomer, and the amount of the polyorganosiloxane block and poly(oxy-2-methyl-1,3-propane) block is determined by the antithrombotic properties of the thermoplastic elastomer. If the content is outside this range, whether it is small or large, it will not be possible to form a microphase-separated structure that is optimal for expressing antithrombotic properties, and the balance between hydrophilicity and hydrophobicity will not be achieved. It collapses and its antithrombotic properties decrease. Next, a platelet adhesion test method performed to evaluate the thermoplastic antithrombotic elastomer obtained according to the present invention will be described. Using the antithrombotic elastomer of the present invention,
A 10% by weight N,N-dimethylacetamide solution was prepared and applied to the inner surface of a sample tube (height: 45 mm, inner diameter: 20 mm) that had been thoroughly washed in advance, and excess solution was removed. Subsequently, it was dried under reduced pressure at 30° C. for about 2 hours, then subjected to ultrasonic cleaning with ethanol, further immersed in ethanol for 24 hours, and then heated and dried under reduced pressure. In conducting the adhesion test of platelets to the sample surface of this sample tube, human whole blood was first immersed in physiological saline for a certain period of time and then collected using citral (sodium citrate) for red blood sedimentation. The volume ratio of blood and chitral is 11:1).
The mixture was dispensed into each sample tube using a 1000 μl micropipette, and shaken for a predetermined time using a shaker (figure 8 shaking, 87 rpm). After shaking, the blood was weighed out using a 20 μl micropipette into a microtube containing 980 μl of Cellkit CD solution (CK-35, manufactured by Toa Medical Electronics Co., Ltd.), and mixed by shaking gently. Centrifugation was performed for 4 minutes using a centrifuge (870 rpm).
Next, take this supernatant liquid, dilute it using an automatic diluter (manufactured by Toa Medical Electronics Co., Ltd., AD-240), and use an automatic platelet counter (manufactured by Toa Medical Electronics Co., Ltd., PL-100). The number of floating platelets was counted. If the number of floating platelets after shaking for a certain period of time is _Nt , and the number of platelets before shaking is No, then the number of platelets N _A adhering to the surface of the sample polymer can be determined by N _A =N - N _t . The same operation is performed using a glass sample tube that is not coated with antithrombotic elastomer to determine the number of platelets N _AG that adhere to the glass surface. From the values of N _A and N _AG , the platelet relative adhesion rate R was expressed as R=N _A /N _AG ×100 (%). The smaller this value is, the better the antithrombotic property is. In addition, Lee et al.
White method [Blood test; P485, Complete book of clinical laboratory techniques
3 (Igaku Shoin) 1979].
A larger value of blood coagulation time indicates better antithrombotic properties. [Example] The present invention will be specifically explained below with reference to Examples. Example 1 4.2 g of poly(oxy-2-methyl-1,3-
propane) diol (number average molecular weight 466 determined from OH value) and 1.8 g of terminal carbinol polydimethylsiloxane (PS-197 manufactured by Chitsuso Co., Ltd., molecular weight 2400) in a four-neck separable tube equipped with a reflux condenser. The mixture was placed in a flask, immersed in a 100°C oil bath, and dehydrated by heating under reduced pressure for 1 hour. After cooling to room temperature, 40 ml of dehydrated and purified N,N-dimethylacetamide was added to form a solution. 50℃
4.95 g of diphenylmethane diisocyanate (recrystallized product) dissolved in 20 ml of N,N-dimethylacetamide was added dropwise. 50℃
After stirring for 1 hour under a dry nitrogen atmosphere, 0.61 g of dehydrated and purified ethylene glycol was added dropwise. After further stirring in the same greenhouse for 3 hours, the reaction product solution was added dropwise into pure water 3 with stirring to solidify and precipitate into flakes. After leaving it overnight, it was separated, and the pure water from step 3 was added again. After repeating this extraction process three times, the sample was immersed in 500 ml of methanol and left overnight. It was then air-dried separately and dried under reduced pressure at 30°C. This sample was further purified by Soxhlet extraction with ethanol as described above, and platelet adhesiveness was evaluated by determining platelet relative adhesiveness. The results are shown in Table 1. Also, Lee
Table 2 shows a comparison of blood coagulation times using the and White method with values for glass plates, soft vinyl chloride, and silicone rubber. Example 2 4.68 g of poly(oxy-2-methyl-1,3-
propane) diol (number average molecular weight 1530 determined from hydroxyl value) and 1.17 g of terminal carbinol polydimethylsiloxane (PS-197 manufactured by Chitsuso Corporation,
(molecular weight 2400) was placed in a four-necked separable flask equipped with a reflux condenser, and vacuum dehydration was performed at 100°C for 1 hour. N, N purified by dehydration after cooling to room temperature
-Add 30ml of dimethylacetamide to make a solution. The mixture was heated to 50°C, and a solution of 1.78 g of diphenylmethane diisocyanate (recrystallized product) dissolved in 10 ml of N,N-dimethylacetamide was added dropwise with stirring, and the reaction was continued for another 1 hour while flowing dry nitrogen. Ta. Subsequently, a solution of 0.97 g of dehydrated purified ethylene glycol and 3.09 g of diphenylmethane diisocyanate (recrystallized product) dissolved in 10 ml of N,N-dimethylacetamide was added dropwise, and the reaction was continued for 3 hours with stirring at 50°C. In the following, the reaction product was purified in the same manner as in Example 1, and platelet relative adhesion rate and Lee
Antithrombotic properties were evaluated by measuring blood coagulation time using the and White method. The results are shown in Tables 1 and 2. Comparative Example 1 Contains polydimethylsiloxane and poly(oxytetramethylene) diol in the same manner as in Example 2, using poly(oxytetramethylene) diol instead of poly(oxy-2-methyl-1,3-propane) diol A thermoplastic polyurethane elastomer was synthesized. That is, 1.2 g of terminal carbinol polydimethylsiloxane (PS-197 manufactured by Chitsuso Corporation, molecular weight 2400), 4.8 g poly(oxytetramethylene) diol (number average molecular weight determined from OH value 1990), and 1.46 g. First, a prepolymer was synthesized from diphenylmethane diisocyanate (recrystallized product) using N,N-dimethylacetamide as a solvent in the same manner as in the example, and then 1.05 g of dehydrated ethylene glycol and 3.50 g of diphenylmethane were synthesized. Similar to Example 1, platelet relative adhesion rate and Lee and
Antithrombotic properties were evaluated by measuring blood coagulation time using the White method. The results are shown in Tables 1 and 2. Compared to the samples of Examples 1 and 2, the results showed inferior antithrombotic properties. Comparative Example 2 As an example of a biomer type segmented polyurethane urea, poly(oxytetramethylene) diol with a number average molecular weight of 1476 determined from the OH value was used as a soft segment, prepolymerized with diphenylmethane diisocyanate, and chain extended with ethylenediamine. Soft segment component amount 72.5
% by weight of segmented polyurethane urea was synthesized, and the purified sample was evaluated for antithrombotic properties by relative platelet adhesion rate in the same manner as in Example 1. As shown in Table 1, the antithrombotic properties were lower than those of the samples of Examples 1 and 2. Comparative Example 3 Number average molecular weight determined from OH value as in Comparative Example 2
A biomer-type segmented polyurethane urea was synthesized using poly(oxytetramethylene) diol of 1980. That is, a prepolymer consisting of poly(oxytetramethylene) diol and diphenylmethane diisocyanate was chain-extended with ethylenediamine, and the soft segment component amount was 77.9.
% by weight of segmented polyurethane urea was obtained. The antithrombotic properties of the purified samples were evaluated based on the platelet relative adhesion rate as in Example 1, and as shown in Table 1, the antithrombotic properties were significantly lower than those of the samples of Examples 1 and 2.

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Claims (1)

[Claims] 1. An organic diisocyanate and a number average molecular weight of 200.
~3000 poly(oxy-2-methyl-1,3-propane) diol and polyorganosiloxane having a number average molecular weight of 200 to 3000 are reacted to produce polyurethane or polyurethane with a soft segment content of 40 to 70% by weight. A method for producing a thermoplastic antithrombotic elastomer, characterized in that a polyurethane urea is obtained. 2. The method for producing a thermoplastic antithrombotic elastomer according to claim 1, wherein the content of soft segments produced from poly(oxy-2-methyl-1,3-propane) diol is 20 to 50% by weight. . 3. The method for producing a thermoplastic antithrombotic elastomer according to claim 1, wherein the content of soft segments produced from polyorganosiloxane is 5 to 30% by weight.